Pancreatic cancer is a lethal malignancy. Even with surgical resection, the recurrence rate is high, and chemotherapy is recommended for all patients due to the systemic nature of the disease. A major treatment challenge is the high rate of resistance to the available treatments. Therefore, there is an urgent need to develop novel treatment modalities with effective and durable responses. Immunotherapy has recently revolutionized the treatment of several malignancies. While these patients have a durable response to immunotherapy and benefit from improved survival, many solid tumors and in particular, pancreatic cancer, do not respond to standard immunotherapy. They do not elicit a significant immune response and are considered immunologically “cold” tumors. A dense tumor microenvironment is a physical barrier against treatment delivery. It also suppresses the immune system to fight against cancer. Therefore, a multi-modality approach targeting tumor cells and tumor microenvironment can overcome treatment resistance more effectively. Converting “cold” tumors to “hot” tumors is an area of great interest in immuno-oncology research. Oncolytic viruses are one of the desirable platforms for this purpose. Their anti-cancer activity is not only the direct killing of tumor cells but also modulating the immune response against cancer. In this project, we have designed novel oncolytic viruses, on a vesicular stomatitis virus backbone, that are bioengineered to express enzymes that target the stroma and tumor microenvironment. In addition, they express antibodies against the immune checkpoint LAG-3. Immune checkpoints inhibit immune response against tumors and by blocking them, they can prevent tumor evasion from the immune system. The combination of LAG-3 inhibition with conventional immune checkpoint inhibitors (PD-1 inhibitors) has been recently shown to enhance immunotherapy efficacy and reverse resistance to PD-1 inhibitors. We hypothesize that this multi-target design offers a comprehensive approach against important resistance mechanisms in pancreatic cancer and not only offers an effective immunotherapeutic approach but also improves the response to available conventional therapies. This study aims to investigate whether targeting the extracellular matrix with the oncolytic virus platform improves anti-tumor toxicity. It determines whether dual targeting of the tumor microenvironment and immune checkpoint inhibition with this oncolytic virus elicits an enhanced immune response. Finally, we will investigate whether combining this novel oncolytic virus with PD-1 inhibitors and standard chemotherapy can elicit safe and effective tumor toxicity and enhanced immune response and if the approach can convert the “cold” tumors to “hot” tumors. Validating our hypothesis in preclinical models provides the required evidence for designing clinical trials that investigate the treatment efficacy and safety of this approach in pancreatic cancer patients. Establishi...